Cocaine use, abuse and dependence is a public health problem that Is directly responsible for hundreds of billions of dollars in health care expenditures per year. Relapse rates to cocaine use are high, creating a pressing need to develop effective therapies for cocaine dependence. As such, this research is important for furthering understanding of cocaine dependence, and for developing effective new treatments. The purpose of this application is to lay the foundation for Dr. Jennifer G. Plebani, Ph.D., a Postdoctoral Fellow at the University of Pennsylvania Center for Studies of Addiction (CSA), to become an independent investigator with expertise in pharmacotherapies for cocaine dependence, and a focus on human laboratory studies. The proposal builds on her existing knowledge of human behavioral laboratory studies for substance dependence, and limited clinical experience in substance dependence through a carefully structured training and research program involving didactic training, coursework, and experiential laboratory training. During the course of this award. Dr. Plebani will build on the postdoctoral mentorship she Is currently receiving from Dr. Helen Pettinati in treating cocaine dependence. She will be mentored by a team of investigators with experience in pharmacotherapies for cocaine (O'Brien and Kampman), human laboratory studies (Oslin), cocaine self-administration studies (Hart), studies of drug-derived reinforcement (Walsh), and statistical analysis and study design for within-subjects cross-over designs (Lynch). The proposed research and training will focus on investigating the determinants and consequences of cocaine dependence via measurement of physiological, behavioral and subjective effects of acute doses of cocaine in human volunteers in the laboratory, and through examination of the effects of pharmacotherapies on the above effects of cocaine. The two studies proposed will examine cocaine-derived reinforcement under week-long sub- chronic varenicline (Chantix) dosing, and under placebo conditions (Study 1), and under week-long sub-chronic Huperzine A dosing, and under placebo conditions (Study 2). Each study is a within- subjects crossover design. This KOI award will allow Dr. Plebani to establish the expertise required to secure ROI funding for future human behavioral pharmacology laboratory studies of cocaine dependence. RELEVANCE (See instructions): Cocaine use, abuse and dependence represent a public health problem that Is directly responsible for hundreds of billions of dollars in health care expenditures per year. As yet, no efficacious pharmacotherapies for cocaine dependence have been found. The goal of this project is to examine the potential efficacy of cholinergic medications in treating cocaine dependence.